Alterations in xenobiotic metabolizing enzymes in brain and liver of rats coexposed to endosulfan and malathion

The effects of endosulfan (3 mg kg-1 body wt., i.p.) and malathion (30 mg kg-1 body wt.) and their coexposure on rat hepatic and brain xenobiotic metabolizing enzymes were investigated. Endosulfan was found to induce aminopyrine-n-demethylase (81%) and aniline hydroxylase (59%) activities significantly in liver and to a lesser extent in brain. Malathion treatment induced malathion carboxylesterase activity in both liver (50%) and brain (22%), significantly depleted liver glutathione (35%) content with stimulation of glutathione-S-transferase (50%) and inhibited the activity of mixed-function oxidases. In the coexposed animals, malathion's inhibitory influence on mixed-function oxidases and endosulfan's inhibitory effect on malathion carboxylesterase were found to dominate, while endosulfan potentiated the activity of glutathione-S-transferase significantly in liver (69%) and brain. A similar trend of alteration in coexposed brain was found, but to a lesser extent. A significant inhibition in brain acetylcholine esterase activity (42%) in the coexposed animals suggests that endosulfan may potentiate the toxicity of malathion by interfering with glutathione and carboxylesterase routes of malathion detoxification.     

Utility of voice therapy in the management of vocal fold polyps and cysts.

OBJECTIVE: To evaluate the efficacy of voice therapy in the management of vocal fold polyps and cysts. STUDY DESIGN AND SETTING: Retrospective review of vocal fold cysts and polyps undergoing voice therapy in a tertiary care center. Symptom resolution or persistence resulting in surgical intervention was the main outcome measure. RESULTS: Fifty-seven patients were identified, of which 49.1% achieved symptom resolution with voice therapy alone. Patients with complete glottal closure and muscle tension dysphonia did not have a better response than those with incomplete glottal closure and without muscle tension dysphonia (P = 0.1, chi(2), respectively). Patients with translucent polyps more commonly responded to voice therapy than fibrotic, hyaline, or hemorrhagic polyps, 81.8% versus 15.4% and 25.0% response rate, respectively (P = 0.002, chi(2)). CONCLUSIONS: Voice therapy is an effective treatment modality for vocal fold polyps and cysts. SIGNIFICANCE: A multidisciplinary approach including a trial of voice therapy is warranted.     

Prevention of sexually transmitted HIV infection: A meta-analytic review of teh behavioral outcome literature

Social learning theory-based models have recently provided the foundation for a series of twelve controlled human immunodeficiency virus (HIV) risk reduction intervention studies that have examined sexual behavior change. These interventions have been tested with adolescents, gay and bisexual men, inner-city women, college students, and seriously mentally ill adults. We report the first meta-analysis of these intervention studies. We found that, as expected, the mean weighted effect of HIV-risk reduction interventions on behavioral outcomes was positive and strongly significant (d₊=0.25). Moreover, the studies’ effect sizes were consistently positive, ranging from 0.11 to 0.53, and were largest when the outcomes were measured close in time to the intervention. We discuss other methodological challenges that, if solved, should enhance the success of future HIV-risk reduction interventions.     

Medication Outcome in ECT-Resistant Depression

The outcome of antidepressant treatment in 12 cases of electroconvulsive therapy (ECT)-resistant depression is presented. Eight patients had been refractory to a clinically adequate course of ECT (Hamilton Depression Scale improvement <20%) and four were partial responders (improvement 20-49%). All remitted completely on antidepressant medication within 2.2 +/- 1.1 (mean +/- SD) months of the ECT course. Remission was associated with clomipramine treatment (139 +/- 49.7 mg/day) in seven cases and maprotiline (125 mg/day) in one case. Four patients who did not respond to a tricyclic antidepressant alone remitted following supplementation (of clomipramine in 2 cases, clomipramine + haloperidol in 1 case, and imipramine in 1 case) with lithium carbonate. Although a delayed therapeutic response to ECT cannot be excluded, the results suggest that ECT may alter the sensitivity of refractory patients to antidepressant medication.     

Monoclonal anti-(T,G)-A—L antibodies: Characterization of fine specificity and idiotype expression

The technique of polyethylene glycol mediated cell fusion was used to establish 22 monoclonal cell lines secreting anti-(T,G)-A—L antibody. Cell lines were derived from C3H.SW and B10 mice and produced antibody with light chains and predominantly γ₁, heavy chains. Fine-specificity analysis demonstrated that 15 cell lines made antibodies that also recognize a determinant present on GAT, GT (9:1) and GT (1:1), whereas little, if any, serum antibody demonstrates this cross-reaction. Fourteen antibodies, derived from both B10 and C3H.SW mice, bear idiotypic determinants defined by Lewis anti-[B10 anti-(T,G)-A—L], but only two, both from C3H.SW mice, react with Lewis anti-[C3H.SW anti-(T,G)-A—L]. Adsorption studies indicate that no hybridoma tested bore the complete set of idiotypic determinants defined by either serum.     

Raised carcinoembryonic antigen level as an indicator of recurrent disease in follow up of patients with colorectal cancer.

BACKGROUND. Serum carcinoembryonic antigen level is raised in 80% of patients undergoing colonic resection for cancer. Subsequent elevation in the follow-up period may precede signs and symptoms as an indicator of recurrent disease. there is little evidence that "classical" follow up of patients in the general surgical outpatient clinic improves either survival or quality of life. Regular carcinoembryonic antigen level estimation requested by the general practitioner, allied to day-case colonoscopic surveillance may be a more rational approach. AIM. A study was undertaken to investigate the relationship between raised carcinoembryonic antigen level and the recurrence of colorectal cancer in patients following a curative primary resection. METHOD. Retrospective analysis was carried out on the notes of 125 patients who had attended a dedicated hospital colorectal follow-up clinic between 1988 and 1992. Carcinoembryonic antigen level data were obtained by subsequent examination of the University of Edinburgh Department of Clinical Chemistry (immunoassay section) carcinoembryonic antigen database. RESULTS. A single carcinoembryonic level result of more than 100 ul-1 (normal range less than 60 ul-1) was found to be a highly sensitive (87%), specific (89%), and accurate (88%) indicator of recurrent disease. Raised carcinoembryonic antigen level preceded symptoms in 72% of patients with recurrence of colorectal cancer. CONCLUSION. Sequential laboratory estimation of carcinoembryonic antigen level organized by the general practitioner may represent an accurate method of detecting recurrent colorectal disease. Hospital review could be limited to colonoscopic surveillance and restaging of patients referred with evidence of recurrent disease.     

Inhibition of platelet adherence to brain microvasculature protects against severe Plasmodium berghei malaria

Some patients with Plasmodium falciparum infections develop cerebral malaria, acute respiratory distress, and shock and ultimately die even though drug therapy has eliminated the parasite from the blood, suggesting that a systemic inflammatory response contributes to malarial pathogenesis. Plasmodium berghei-infected mice are a well-recognized model of severe malaria (experimental severe malaria [ESM]), and infected mice exhibit a systemic inflammatory response. Because platelets are proposed to contribute to ESM and other systemic inflammatory responses, we determined whether platelet adherence contributes to experimental malarial pathogenesis. Indeed, a significant (P < 0.005) increase in the number of rolling and adherent platelets was observed by intravital microscopy in brain venules of P. berghei-infected mice compared with the number in uninfected controls. P-selectin- or ICAM-1-deficient mice exhibit increased survival after P. berghei infection. We observed a significant (P < 0.0001) reduction in the morbidity of mice injected with anti-CD41 (alpha(IIb) or gpIIb) monoclonal antibody on day 1 of P. berghei infection compared with the morbidity of infected controls injected with rat immunoglobulin G. Additionally, platelet rolling and adhesion in brain venules were reduced in P. berghei mice lacking either P-selectin or ICAM-1 or when the platelets were coated with anti-CD41 monoclonal antibody. Unlike other inflammatory conditions, we did not detect platelet-leukocyte interactions during P. berghei malaria. Because (i). leukocyte adhesion is not markedly altered in the absence of P-selectin or ICAM-1 and (ii). CD41 is not an adhesion molecule for parasitized erythrocytes, these findings support the hypothesis that inhibition of platelet adhesion to the brain microvasculature protects against development of malarial pathogenesis.     

Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency

Systemic primary carnitine deficiency (CDSP, OMIM 212140) is an autosomal recessive disease characterized by low serum and intracellular concentrations of carnitine. CDSP may present with acute metabolic derangement simulating Reye's syndrome within the first 2 years of life. After 3 years of age, patients with CDSP may present with cardiomyopathy and muscle weakness. A linkage with D5S436 in 5q was reported in a family. A recently cloned homologue of the organic cation transporter, OCTN2, which has sodium-dependent carnitine uptake properties, was also mapped to the same locus. We screened for mutation in OCTN2 in a confirmed CDSP family. One truncating mutation (Trp132Stop) and one missense mutation (Pro478Leu) of OCTN2 were identified together with two silent polymorphisms. Expression of the mutant cDNAs revealed virtually no uptake activity for both mutations. Our data indicate that mutations in OCTN2 are responsible for CDSP. Identification of the underlying gene in this disease will allow rapid detection of carriers and postnatal diagnosis of affected patients.     

Intestinal antilectin immunoglobulin A antibody response and immunity to Entamoeba dispar infection following cure of amebic liver abscess

We followed 93 subjects with amebic liver abscess (ALA) and 963 close associate controls at 3-month intervals for 36 months to characterize intestinal and humoral antibody responses to the amebic galactose-inhibitable lectin and to determine whether immunity developed to Entamoeba histolytica or Entamoeba dispar infection following cure of ALA. We found that ALA subjects had a higher prevalence and level of intestinal antilectin immunoglobulin A (IgA) and serum anti-LC3 (cysteine-rich recombinant lectin protein) IgA and IgG antibodies, P < 0.01 and P < 0.05, respectively, compared to controls. The intestinal antilectin IgA antibody response was sustained over a longer time period in ALA subjects (71.8% remained positive at 18 months and 52.6% at 36 months, P < 0.001 compared to 17.6% and 10.3% of controls, respectively). ALA subjects were highly immune to E. dispar infection throughout the study (0% infected at 6 and 36 months, compared to 6.5% and 4.9% of control subjects, respectively, P < 0.05). Upon entry into the study, 6.3% of ALA subjects were infected with E. histolytica; the incidence of new E. histolytica infections in controls (as determined by culture) was too low (1.4%) to determine whether ALA subjects exhibited immunity to new infections. We found that stool cultures every 3 months markedly underestimated the occurrence of new E. histolytica infections, as 15.3% of controls seroconverted after 12 months of follow-up. Unfortunately, under the field conditions present in Durban, South Africa, enzyme-linked immunosorbent assay for detection of lectin antigen in stool yielded unreliable results. In summary, subjects cured of ALA exhibited sustained mucosal IgA antibody responses to the amebic galactose-inhibitable lectin and a high level of immunity to E. dispar infection. Determination of immunity to E. histolytica following cure of ALA will require the use of more sensitive and reliable diagnostic methods.